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Has the Effectiveness of Lithium Changed? Impact of the Variety of Lithium’S Effects Paul Grof, M.D., Ph.D

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Has the Effectiveness of Lithium Changed? Impact of the Variety of Lithium’S Effects Paul Grof, M.D., Ph.D Has the Effectiveness of Lithium Changed? Impact of the Variety of Lithium’s Effects Paul Grof, M.D., Ph.D. Lithium treatment, initially considered specific for bipolar accumulation of atypical, treatment-resistant patients in disorder, has since been shown to provide additional benefits academic centers and, in particular, the broadening of in affective and other disorders. This variety of benefits diagnoses of affective disorders, further complicate the should be taken into account when interpreting recently interpretation of the recent reports. Lithium, however, reported lower efficacy during lithium prophylaxis, as well continues working well for patients with typical bipolar as early relapses and loss of efficacy after lithium disorders, for whom it was originally proved effective. discontinuation. There are particularly striking parallels [Neuropsychopharmacology 19:183–188, 1998] between these recent reports and earlier observations of © 1998 American College of Neuropsychopharmacology. “antipsychotic” lithium effects. Other factors, such as the Published by Elsevier Science Inc. KEY WORDS: Lithium effects; Prophylactic effect; that when bipolar and unipolar patients stabilized on Antipsychotic effect; Lower efficacy of lithium; lithium were randomly allocated to lithium and pla- Discontinuation of lithium; Loss of efficacy cebo, only the placebo patients subsequently relapsed. It has been nearly 50 years since John Cade (1949) first In addition to its demonstrated efficacy, lithium was reported on the specific treatment of acute mania with also thought to be a specific drug for manic-depressive lithium salts and about 25 years since lithium was illness. Cade was so struck by the specificity that he en- widely accepted as an effective long-term treatment. tertained the possibility of lithium deficiency in his pa- When lithium treatment first achieved wide acceptance, tients. Later, the conviction about specificity was drawn it was welcomed as a treatment that had the best dem- mainly from the initial observations that lithium could onstrated efficacy among psychiatric treatments. A se- prevent recurrences of primary affective disorders but ries of double-blind as well as large open studies (as re- not of other psychiatric conditions, and at the same viewed, for example, in Schou and Thomsen 1975; time, had only negligible effects on normal moods. Schou 1982) demonstrated uniformly lithium’s useful- Lithium seemed to be a substance with a specific bene- ness, as well as its superiority over a placebo and anti- fit, when compared with the broad spectrum of applica- depressants in the long-term treatment of affective dis- tions of other psychotropic agents. For example, tricy- orders. The double-blind discontinuation study of clic antidepressants could treat conditions as varied as Baastrup et al. (1970) presented particularly robust mental depression, chronic pain, and nocturnal enure- findings, unparalleled in psychiatry, which showed sis. This tenet of lithium’s specificity was so mighty that clinicians often tended to conclude ex iuvantibus; when patients treated with lithium benefited, it was resolved that they must be suffering from some form of bipolar From the Department of Psychiatry, University of Ottawa, Royal illness. In hindsight, it would have been more produc- Ottawa Hospital, 1145 Carling Avenue, Ottawa, Ontario, Canada. tive to question lithium’s absolute specificity. Address correspondence to: P. Grof, M.D., Ph.D., Department of Psychiatry, University of Ottawa, Ottawa, ONT K1Z 7K4, Canada. Over the years, however, the initially narrow scope Received February 23, 1998; accepted February 23, 1998. of lithium’s caliber in affective disorders has quickly ex- NEUROPSYCHOPHARMACOLOGY 1998–VOL. 19, NO. 3 © 1998 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/98/$19.00 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(98)00023-2 184 P. Grof NEUROPSYCHOPHARMACOLOGY 1998–VOL. 19, NO. 3 panded, adding to its well-established antimanic and quency. Second, both expected manias and expected prophylactic benefits antiaggressive effects (particu- depressions were significantly reduced. Third, the pro- larly studies of Sheard 1978, 1984), antipsychotic poten- phylactic effect was dependent upon therapeutic lith- tial (e.g., investigations of Garver et al. 1988; Garver ium concentrations, and toxicity was observed only Hutchinson 1988; Lenz et al. 1987, Lenz et al. 1989), an- with elevated lithium levels. Fourth, when lithium tisuicidal and mortality-reducing ability (specifically, treatment was discontinued in remission, subsequent studies of Müller-Oerlinghausen et al. 1992; Coppen et recurrences developed gradually, and no rebound was al. 1992), and possibly also antidepressant (Mendels observed. The benefit was generally reproducible by re- 1976, 1982) and antidepressant-augmenting effects (de instituting lithium treatment. Montigny et al. 1983). Surprisingly, while quickly expanding therapeutic Antimanic Effect horizons, lithium has also been reported to be gradually less and less effective (Grof et al. 1993; Guscott and Tay- The value of lithium as an antimanic drug has been well lor 1994), particularly in clinical practice. Recent litera- established against a placebo and neuroleptics; there- ture certainly paints a rather pessimistic picture; it fore, lithium is now considered the standard antimanic seems now that only a fraction of patients actually ben- drug. Similar to the current controversy about lithium’s efit from lithium prophylaxis (Prien and Gelenberg prophylactic efficacy, recent findings about the anti- 1989), and a sizeable proportion of patients may lose manic effects of lithium have been less uniform, some the benefit altogether over time (Post et al. 1992). Fur- confirming (Bowden et al. 1994) and others questioning thermore, discontinuation of lithium is often followed lithium’s superiority over placebo. The issue of whether by a prompt recurrence of the illness (Suppes et al. the prophylactic and antimanic benefits are of the same 1991), and later possibly by a loss of efficacy (Post et al. nature and exert themselves in the same patients has 1992). In brief, recent literature suggests that although not yet been systematically investigated. Clinically, lithium treatment does not help much anymore, after its there seems to be an association. However, the anti- discontinuation, many patients may now suffer even manic effect at times seems to act with a wider range, as more. if there were at least two possible mechanisms in- Thus, during the past two decades, the earlier per- volved: a relatively specific effect in bipolar mania; and ception of lithium as an effective and specific treatment a nonspecific, overactivity-reducing effect in some has been changing from that of a highly valued, long- pathological states of other provenience. Further under- term treatment to a questionably useful substance of standing of lithium’s antimanic activity may surface fleeting benefit. It is important to explore the nature of from the emerging comparative studies with such anti- this shift and the possible misunderstandings that sur- epileptics as valproic acid and lamotrigine. round it. We suggest that a combination of several fac- tors has contributed to this controversy, in particular a Antiaggressive Effect lack of recognition that lithium treatment offers more than one distinct clinical benefit; a broadening of the di- The antiaggressive effects of lithium have been demon- agnoses of affective disorders; the need to differentiate strated amply in a series of studies, in particular, between efficacy and effectiveness; and an accumula- Sheard (1978, 1984). The effects were documented in tion of difficult-to-treat affective disorders in academic several different populations: psychiatric patients, men- research centers. tally retarded populations, and penitentiary subjects. Sheard and other investigators who studied the antiag- gressive effects of lithium argued convincingly that VARIETY OF LITHIUM EFFECTS subjects who benefited did not suffer from bipolar ill- ness: the effect was distinctly different. A variety of distinct effects of lithium treatment have been described, along with their clinical characteristics. “Antipsychotic” Effect In terms of lithium’s specificity, probably one of the “Prophylactic,” Normal Mood Stabilizing Effect most perplexing effects of lithium has been its “antipsy- The important clinical characteristics of this most chotic” capacity. Both acute and long-term “antipsy- widely utilized, well-documented benefit have been chotic” effects have been described best by Garver and outlined, in particular, in the large series of the studies his group (Garver et al. 1984, 1988) in schizophrenias of lithium in the late 1960s and early 1970s. First, the re- and schizophreniform psychoses, and illustrated on currences of abnormal moods were significantly re- schizoaffective psychoses by many others (e.g., Angst et duced in about three-quarters of the patients, either al. 1970; Lenz et al. 1987; Lenz et al. 1989) and can com- suppressed completely or reduced substantially in fre- monly be seen clinically. During treatment with lithium NEUROPSYCHOPHARMACOLOGY 1998–VOL. 19, NO. 3 Has Effectiveness of Lithium Changed? 185 alone, a dramatic clearing of psychotic symptoms has edly reduces mortality and suicidal behavior and that been seen in acute psychoses (schizoaffective and schizo- the mortality of affective disorders is diminished to
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